Presenilin1 (PS1), is a polytopic integral membrane protein that plays important roles in the development of familial Alzheimer's disease (FAD). Classic cadherins are type I transmembrane glycoproteins that control critical events in cell adhesion, recognition, and contact-mediated inhibition of cell growth. Recently we reported that PS1 concentrates at cell-cell and synaptic contact sites where it incorporates into the cadherin/catenin cell-cell adhesion system. Here we present preliminary data that PS1 binds directly to E-cadherin and regulates Ca++-dependent cell-cell adhesion. In addition, our results indicate that PS1 and a gamma-secretase activity control production of a cadherin cytoplasmic peptide of about 20kDa (termed pC20) and regulate expression of both cyclin D1 and cyclin-dependent kinase inhibitor p27Kip1, two important cell cycle proteins. pC20 seems to be derived from a larger cadherin precursor termed pC35. pC35 is produced following an extracytoplasmic cleavage of the full length cadherin. Expression of a cadherin cytoplasmic peptide in PS1-deficient cells mimicked the pC20 effects and reduced the expression levels of both cyclin D1 and p27Kip1. Taken together, our preliminary data suggest that PS1, cadherins, and gamma-secretase are involved in a novel signal transduction mechanism that regulates expression of cell cycle proteins. This mechanism may use the cytoplasmic cadherin-derived peptide pC20 as a messenger which translocates to the nucleus where it controls expression of cell cycle proteins. PS1 and gamma-secretase activity may thus control the cadherin signal transduction pathway by regulating expression of the cadherin-derived message. This application proposes to characterize the cadherin-PS1-gamma-secretase signal transduction pathway and to examine its involvement in Alzheimer's disease.